The identification of receptors for cannabinoids allowed a search for endogenous ligands that was rewarded by the discovery that an arachidonic acid derivative, arachidonoyl ethanolamide, bound with high affinity to the CB1 receptor.

This compound, which is called anandamide (from the Sanskrit ‘a-nanda’ : meaning, ‘happiness, joy, enjoyment, sensual pleasure ’) had pharmacological and behavioural effects very similar to D9-tetrahydrocannabinol.

Cannabinoids metabolism

The synthetic pathway involves breaking down the membrane phospholipid precursor, N-arachidonoyl phosphatidylethanolamine, to yield anandamide by a phospholipase enzyme.

Inactivation of anandamide is by re-uptake through a specific carrier followed by hydrolysis by fatty acid amide hydrolase.
The precursor of anandamide (N-arachidonoyl phosphatidylethanolamine) is synthesised by Ca2+ - dependent trans-acylation of phosphatidylethanolamine and the arachidonate is thought to be donated by 1,2-sn-diarachidonoyl phosphatidylcholine.

Two other endogenous compounds, 2-arachidonoylglycerol(2-AG) and the structurally related 2-arachidonoylglyceryl ether also been found to bind to cannabinoid sites.

2-AG has been proposed as being the endogenous agonist for the CB2 receptor and is synthetised from the signalling molecule 1,2-sn-diacylglycerol (DAG) by DAG lipase.
Unlike anandamide, there does not appear to be a facilitated transport system for 2-AG.

There are several other putative endocannabinoids described in the literature.
These include

Interestingly, the arachidonic acid derivative N-arachidonoylglycine acts to suppress pain, which is often associated with agonist activity at CB1 receptors, but has no affinity for this cannabinoid receptor.

Regulation of Cannabinoids metabolism

That anandamide might be an endogenous mediator is supported by the observation that depolarised rat brain neurons in culture produced it.